At a Glance

Cyclooxygenase (CO) deficiency is a mild to moderate bleeding disorder in which the primary defect is a quantitative deficiency of the enzyme cyclooxygenase, ultimately leading to reduced thromboxane production.

CO deficiency is extremely rare and can lead to both a thrombotic and bleeding phenotype. CO deficiency is characterized by mucocutaneous, GI or surgical bleeding, as well as cerebrovascular and cardiac events (atherosclerosis).

CO deficiency is categorized into 2 subtypes.

After platelets adhere to the damaged endothelium, mediated through von Willebrand factor (VWF), and aggregate, mediated through fibrinogen, the recruited platelets activate and liberate their stored granules. Thromboxane production provides positive feedback to granule secretion and assists in platelet aggregation through not fully elucidated mechanisms.

The diagnosis of CO deficiency can be made by demonstration of impaired secondary wave aggregation to low dose adenosine diphosphate (ADP) impaired aggregation to collagen and epinephrine, and absent aggregation to arachidonic acid using platelet aggregometry. The platelet function analyzer-100 (PFA-100; an in vitro assessment of the qualitative platelet function) pattern will look similar to recent aspirin use with only prolongation of closure time of the collagen/epinephrine. (Table 1)

Table 1.

Subtypes of Cyclooxygenase deficiency

Type I CO deficiency

Type II CO deficiency

-Undetectable enzyme activity

-Low enzyme antigen

-Normal antigen levels

-Defective enzyme activity

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

If there is clinical suspicion for CO deficiency, then it would be recommended to first rule out other bleeding disorders prior to verification of this rare diagnosis. A reasonable screening hemostatic evaluation should include the following labs:

complete blood count (CBC) with differential

peripheral blood smear

PFA-100

Prothrombin time (PT)

Partial thromboplastin time (PTT)

fibrinogen activity

Direct evaluation for von Willebrand disease (VWD) by VWF antigen, Ristocetin cofactor assay, and factor 8 (FVIII) activity should be considered upfront, especially if there are mucocutaneous bleeding symptoms.

With CO deficiency, there are no associated cytopenias and the platelets have a normal morphological appearance under light microscopy. Screening PT/PTT and fibrinogen activity will be normal. The closure time in a PFA-100 will be prolonged in the collagen/epinephrine cartridge only.

If the collagen/epinephrine cartridge PFA-100 is solely prolonged with an otherwise negative hemostatic workup, then consideration of a platelet aggregometry is reasonable. (Table 2)

Table 2.

Test Results Indicative of the Disorder

PFA-100

Platelet aggregometry

Cyclooxygenase enzyme activity

Prolonged closure time with the collagen/epinephrine cartridge

Impaired secondary wave aggregation to low dose ADP

Deficient activity

Impaired aggregation to collagen/epinephrine

Absent aggregation to arachidonic acid

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

A thorough drug history is recommended prior to performing a PFA-100 or other platelet studies, since recent non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin use (within the preceding 7-8 days) can lead to false-positive results. In addition, there are herbal medications and certain foods (e.g., garlic and fatty foods) that can prolong the closure time in the collagen/epinephrine cartridge.

What Lab Results Are Absolutely Confirmatory?

In the absence of recent aspirin or NSAID use, demonstration of impaired secondary wave aggregation to low dose ADP, impaired aggregation to collagen and epinephrine, and absent aggregation to arachidonic acid, platelet lumiaggregometry is the gold standard test for diagnosis of CO deficiency.

Chemiluminescent or radioimmunossay CO activity assays can be done by expert labs to verify a diagnosis of CO deficiency.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

For CO deficiency, the platelet response is similar as those with thromboxane synthetase deficiency, thus, clarification with quantification of the CO enzyme activity is warranted.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

The PFA-100 cannot be used to rule out a CO deficiency, and, if there is strong clinical suspicion, platelet lumiaggregometry is recommended with subsequent quantification of CO activity.